Cancer is regarded as a disease in the intracellular signal transduction system or in the mechanism of the signal transduction. The cell accepts many extracellular orders and decides whether or not to proliferate. The aim of the signal transduction system is to accept these or other signals from the cell surface, and to transfer them into cells. And then these signals are conducted to cell nucleus, cytoskeleton and the structure for transportation and protein synthesis. The most common pathogenesis for cancer is a series of defects.
The mentioned defects can be that of some proteins (when mutation occurs) or the defects in the regulation of the amount of the intracellular protein, which result in excessive or deficient production of the proteins. Generally, the constitutive state can be induced by a significant trauma in a cell, and a signal for proliferation is thus received by the cell nucleus, while this signal is inexistent in fact. The above mentioned procedure can be mediated by many kinds of mechanisms. Sometimes, some cells will start producing true growth factors for their own receptors in unnecessary cases, which is so-called autocrine loop mechanism.
There are many receptors on the cell surface. The interaction between the growth factors and these receptors is essential for the regulation of normal cellular growth. However, in some cases, the overexpression or mutation of the abnormal receptors will result in uncontrollable proliferation, which may induce tumor growth and cancer at last.
Epidermal cell growth factors receptors (EGFR) are identified as one significant driving factor in the process for cellular growth and proliferation. In common cancer, such as non-small cell lung cancer, the epidermal cell growth factors receptors are expressed excessively far above the normal level. The epidermal cell growth factors receptors family is composed of EGFR (Erb-B1), Erb-B2 (HER-2/neu), Erb-B3 and Erb-B4. The epidermal cell growth factors receptors are concerned in the process for most cancer, especially colon cancer and breast cancer. The overexpression and mutation of the receptors have been proved to be the leading risk factor for a bad-prognosis breast cancer. Besides, it has been verified that each of the above four members of the receptors family can aggregate with another member into a heterodimer, and form a signal delivery complex. Overexpression of more than one member of this family in a malignant tumor will result in a synergistic signal delivery.
EGFR belongs to the protein tyrosine kinase (PTK) family. The protein tyrosine kinase is an enzyme which catalyzes the transportation of phosphate groups from ATP to the tyrosine residue located in a protein substrate. Protein tyrosine kinases play important roles in normal cell growth. The overexpression of EGFR may cause the activation of receptors without ligands and the phosphorylation 25 of some proteins, and then the signal for cell division is produced. As a result, EGFR may magnify the weak signal excessively by the auto-tyrosine-kinase action, and render the overproliferation of cells.
Due to the importantance of the abnormal receptor kinases in the mechanism for the onset of cancer, many researches have been involved in searching for specific PTK inhibitors as potential anti-cancer drugs recently. European patent application 520722A1 discloses certain 4-phenylamino-phthalazinone derivatives with inhibitory activity against PTK. European patent application 566226A1 discloses some 4-phenylamino-phthalazinone derivatives with substituents at position 5 to position 8 having PTK inhibitory activity. European patent application 635498A1 discloses that certain 4-phenylamino-phthalazinone derivatives with various substituents at position 6 and with a halogen at position 7 also possess PTK inhibitory activity.
The international publication WO96/30347 (Chinese patent CN96102992) relates to a series of 4-(substituted-phenylamino) -quinazoline derivatives, the prodrugs and the pharmaceutical acceptable salts thereof, which are used in treating diseases induced by overproliferation.
The international publication WO97/38983 (Chinese patent CN97194458) provides the compounds useful as irreversible 15 inhibitors against tyrosine kinase.
The international publication WO 00/06555 (Chinese patent CN99808949) also relates to certain substituted quinazoline compounds that possess PTK inhibitory activity.
The international publication WO 99/35146 (Chinese patent 20 CN99803887) discloses bicycloheteroaromatics as inhibitors against protein tyrosine kinase.
However, there remains the need in this field for new inhibitors effective against protein tyrosine kinases.